Interleukin-21 enhances NK cell activation in response to antibody-coated targets

Julie M. Roda, Robin Parihar, Amy Lehman, Aruna Mani, Susheela Tridandapani, William E. Carson

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

NK cells express an activating FcR (FcγRIIIa) that mediates Ab-dependent cellular cytotoxicity and the production of immune modelatory cytokines in response to Ab-coated targets. IL-21 has antitumor activity in murine models that depends in part on its ability to promote NK cell cytotoxicity and IFN-γ secretion. We hypothesized that the NK cell response to FcR stimulation would be enhanced by the administration of IL-21. Human NK cells cultured with IL-21 and immobilized IgG or human breast cancer cells coated with a therapeutic mAb (trastuzumab) secreted large amounts of IFN-γ. Increased secretion of TNF-α and the chemokines IL-8, MIP-1α, and RANTES was also observed under these conditions. NK cell IFN-γ production was dependent on distinct signals mediated by the IL-21R and the FcR and was abrogated in STAT1-deficient NK cells. Supernatants derived from NK cells that had been stimulated with IL-21 and mAb-coated breast cancer cells were able to drive the migration of naive and activated T cells in an in vitro chemotaxis assay. IL-21 also enhanced NK cell lytic activity against Ab-coated tumor cells. Coadministration of IL-21 and Ab-coated tumor cells to immunocompetent mice led to synergistic production of IFN-γ by NK cells. Furthermore, the administration of IL-21 augmented the effects of an anti-HER2/neu mAb in a murine tumor model, an effect that required IFN-γ. These findings demonstrate that IL-21 significantly enhances the NK cell response to Ab-coated targets and suggest that IL-21 would be an effective adjuvant to administer in combination with therapeutic mAbs.

Original languageEnglish (US)
Pages (from-to)120-129
Number of pages10
JournalJournal of Immunology
Volume177
Issue number1
StatePublished - Jul 1 2006
Externally publishedYes

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Natural Killer Cells
Antibody Formation
interleukin-21
Breast Neoplasms
Chemokine CCL5
Neoplasms
Aptitude
Chemotaxis
Interleukin-8
Chemokines
Immunoglobulin G
Cytokines
T-Lymphocytes
Therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

Roda, J. M., Parihar, R., Lehman, A., Mani, A., Tridandapani, S., & Carson, W. E. (2006). Interleukin-21 enhances NK cell activation in response to antibody-coated targets. Journal of Immunology, 177(1), 120-129.

Interleukin-21 enhances NK cell activation in response to antibody-coated targets. / Roda, Julie M.; Parihar, Robin; Lehman, Amy; Mani, Aruna; Tridandapani, Susheela; Carson, William E.

In: Journal of Immunology, Vol. 177, No. 1, 01.07.2006, p. 120-129.

Research output: Contribution to journalArticle

Roda, JM, Parihar, R, Lehman, A, Mani, A, Tridandapani, S & Carson, WE 2006, 'Interleukin-21 enhances NK cell activation in response to antibody-coated targets', Journal of Immunology, vol. 177, no. 1, pp. 120-129.
Roda JM, Parihar R, Lehman A, Mani A, Tridandapani S, Carson WE. Interleukin-21 enhances NK cell activation in response to antibody-coated targets. Journal of Immunology. 2006 Jul 1;177(1):120-129.
Roda, Julie M. ; Parihar, Robin ; Lehman, Amy ; Mani, Aruna ; Tridandapani, Susheela ; Carson, William E. / Interleukin-21 enhances NK cell activation in response to antibody-coated targets. In: Journal of Immunology. 2006 ; Vol. 177, No. 1. pp. 120-129.
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